Optimal Dose and Cost-effectiveness of Ranibizumab Treatment of Diabetic Macular Oedema

European Ophthalmic Review, 2016;10(2):125–31 DOI: https://doi.org/10.17925/EOR.2016.10.02.125


A key treatment for diabetic macular oedema (DMO) is ranibizumab (Lucentis®), which is approved at differing doses: 0.5 mg/month in Europe and 0.3 mg/month in the US. The relative efficacy and safety of these doses, however, is a controversial issue. A wide ranging literature search was conducted to examine the evidence supporting these doses. The searches identified only four studies that evaluated the 0.3 mg ranibizumab dose, in which best-corrected visual acuity (BCVA) improvements ranged from +5.7 to +12.8 letters during treatment. The searches also identified 12 key studies that evaluated the 0.5 mg dose of ranibizumab, in which BCVA improvement ranged from +6.1 to +10.3 letters. The pivotal RIDE and RISE studies (n=382 and 377) were the only direct comparisons of the 0.3 mg and 0.5 mg ranibizumab doses and placebo. A pooled analysis of these studies showed that improvements in BCVA were numerically higher for the 0.3 mg-treated groups than for the 0.5 mg-treated groups at 24 and 36 months. Patients who were initially treated with sham injections and switched to ranibizumab did not match the improvements in those treated from the start. There was also little difference in central retinal thickness reduction between the two doses (261.8 and 261.2 μm versus 266.7 and 269.1 μm). Ranibizumab was well tolerated, adverse events occurred at similar frequencies in all groups, with a slightly greater incidence of stroke for the 0.5 mg dose. Analysis of RIDE and RISE also showed that ranibizumab is cost-effective. Overall, the data indicate that the 0.3 mg dose of ranibizumab is generally as effective as the 0.5 mg dose in DMO treatment.
Keywords: Ranibizumab, diabetic macular oedema,cost-effectiveness
Disclosure: Jean-Francois Korobelnik has been a consultant for Alcon, Alimera, Allergan, Bayer, Horus, Novartis, Roche, Théa and Zeiss.
Compliance with Ethics Guidelines: This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.
Acknowledgments: Medical writing assistance was provided by James Gilbart, Touch Medical Media.
Authorship:All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.
Received: September 14, 2016 Accepted November 16, 2016
Correspondence: Jean-Francois Korobelnik, Department of Ophthalmology, CHU de Bordeaux, Hopital Pellegrin, Place Amélie Raba Léon, 33000 Bordeaux, France. E: jean-francois.korobelnik@chu-bordeaux.fr
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.

Diabetic macular oedema (DMO) is an increasingly serious healthcare issue and a leading cause of blindness worldwide.1 Of the estimated 415 million people with diabetes globally, 7–12% have signs of DMO and 1–3% have visual impairment as a result.2,3 This burden affects populations in all territories and is likely to increase substantially when the prevalence of diabetes burgeons to a predicted 642 million by 2040.2–4 The availability of effective and tolerable treatments for the management of DMO is therefore critical in tackling a potential epidemic of blindness and visual impairment. Several treatments are available for DMO, including laser photocoagulation, intravitreal corticosteroids and anti-vascular endothelial growth factor (VEGF) agents. Prominent among the anti-VEGF agents is ranibizumab (Lucentis®, Genentech, California, US), which has an extensive body of clinical trial data supporting its efficacy and tolerability in DMO, and on which its approval by the US Food and Drug Administration and the European medicines Agency for use in this indication is based.5–10 This monoclonal antibody (MAb) treatment has been used successfully as monotherapy and in combination with laser photocoagulation and with other treatments.11–19 Manufacturing biological therapies, including MAbs, is an expensive process and their generally high cost has the potential to restrict usage in many territories, especially where healthcare resources are limited.20–22 Reducing the dose of MAbs could lower this cost, provided that efficacy is not compromised markedly. Currently the licensed dose for ranibizumab in DMO in Europe is 0.5 mg/month as an intravitreal injection. In the US, however, the licensed dose is 0.3 mg/month due to concerns of cardiovascular risks in diabetic patients. This article reports the findings of literature searches of clinical studies that investigated the comparative efficacy and safety and cost-effectiveness of the 0.5 mg dose of ranibizumab in DMO compared with the lower 0.3 mg dose. These searches aimed to identify if there was superior efficacy in terms of visual acuity (VA) and central retinal thickness (CRT) or safety for either dose level in DMO treatment and whether the lower dose could be used as an alternative in many cases and thereby reduce costs.

Literature search methods and results
Combined searches were made in BIOSIS Previews®, British Library Inside Conferences, Embase®, Embase® Alerts and MEDLINE®, with no date restriction. Title and abstract terms searched for included MeSH terms for clinical studies in DMO, or diabetic retinopathy restricted to ranibizumab and 0.5 mg or 0.3 mg. In total, 157 unique references were identified. After removal of irrelevant articles and duplicate reports of the same studies, 47 relevant studies were identified. Of these, four studies included groups given only 0.3 mg ranibizumab as a comparator or single therapy, 28 studies included groups given only 0.5 mg ranibizumab and only two studies directly compared the 0.3 mg and 0.5 mg ranibizumab doses. The designs, patient dispositions and findings of these categories are summarised in Tables 1, 2 and 3 (only completed studies with >40 patients for the ranibizumab 0.5 mg dose are tabulated).

The effect of different ranibizumab dosing regimens, the efficacy of ranibizumab compared with other treatments for DMO and in combination with other agents is outside the scope of this article.

Studies including only a 0.3 mg ranibizumab dose group – in diabetic macular oedema
There have been few studies that evaluated the 0.3 mg ranibizumab dose as a discrete group in the treatment of DMO (see Table 1). The four relevant studies ranged from 22 to 666 patients in size (mean 222 patients) and treatment durations varying from three months to two years.23–26 In three of the studies, ranibizumab monotherapy was a comparator against alflibercept, or bevacizumab or compared or in combination with AKB-9778 (a small-molecule competitive inhibitor of vascular endothelial-protein tyrosine phosphatase).23,25,26 One study was a retrospective chart review.24 Treatment durations were from one month to two years, during which best-correct visual acuity (BCVA) improved from +5.7 to +12.8 letters and improvements in VA. In one study there were no significant differences at the end of two years in VA for ranibizumab 0.3 mg compared with aflibercept 2.0 mg or bevacizumab 1.25 mg (p=0.18 for both) for patients with worse baseline VA (20/50 to 20/320).25 Results were similar in patients with better baseline VA (20/32 to 20/40). In another study ranibizumab 0.3 mg was significantly better than bevacizumab 1.25 mg in terms of VA -6.6 letters versus 5.3 letters (p=0.039).26 Reductions in CRT were -89 and -137 μm during treatment for bevacizumab and ranibizumab, respectively (p=<0.001). The ranibizumab treatment in these studies was well tolerated with no new adverse events profiles, i.e., these profiles being similar to those reported for the phase III studies.27,28

These studies had varying designs, study endpoints, patient populations and treatment durations, making direct comparisons difficult. However, a strong overall message that emerges from these studies is that 0.3 mg dose of ranibizumab is effective and has potential as a clinical treatment in DMO which was similar to or superior to that of some other treatments.

1. Ding J, Wong TY, Current epidemiology of diabetic retinopathy and diabetic macular edema, Curr Diab Rep, 2012;12:346–54.
2. International Diabetes Federation, IDF Diabetes Atlas, 7th edition. Available at: www.diabetesatlas.org/ (accessed 4 July 2016). 3. Chen E, Looman M, Laouri M, et al., Burden of illness of diabetic macular edema: literature review, Curr Med Res Opin, 2010;26:1587–97.
4. Sabanayagam C, Yip W, Ting DS, et al., Ten Emerging Trends in the Epidemiology of Diabetic Retinopathy, Ophthalmic Epidemiol, 2016;1–14.
5. Dedania VS, Bakri SJ, Current perspectives on ranibizumab, Clin Ophthalmol, 2015;9:533–42.
6. Fong AH, Lai TY, Long-term effectiveness of ranibizumab for age-related macular degeneration and diabetic macular edema, Clin Interv Aging, 2013;8:467–83.
7. Frampton JE, Ranibizumab: in diabetic macular oedema, Drugs, 2012;72:509–23.
8. Krispel C, Rodrigues M, Xin X, et al., Ranibizumab in diabetic macular edema, World J Diabetes, 2013;4:310–8.
9. Wang H, Sun X, Liu K, et al., Intravitreal ranibizumab (lucentis) for the treatment of diabetic macular edema: a systematic review and meta-analysis of randomized clinical control trials, Curr Eye Res, 2012;37:661–70.
10. Yanagida Y, Ueta T, Systemic safety of ranibizumab for diabetic macular edema: meta-analysis of randomized trials, Retina, 2014;34:629–35.
11. Berger A, Sheidow T, Cruess AF, et al., Efficacy/safety of ranibizumab monotherapy or with laser versus laser monotherapy in DME, Canadian journal of ophthalmology, Can J Ophthalmol, 2015;50:209–16.
12. Bressler SB, Glassman AR, Almukhtar T, et al., Five-Year Outcomes of Ranibizumab With Prompt or Deferred Laser Versus Laser or Triamcinolone Plus Deferred Ranibizumab for Diabetic Macular Edema, Am J Ophthalmol, 2016;164:57–68.
13. Chong V, Mitchell P, Baseline predictors of 3-year responses to ranibizumab and laser photocoagulation therapy in patients with visual impairment due to diabetic macular edema (DME), Eur J Ophthalmol, 2013;23:453–4.
14. Elman MJ, Aiello LP, Beck RW, et al., Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema, Ophthalmology, 2010;117:1064–77.e35.
15. Elman MJ, Ayala A, Bressler NM, et al., Intravitreal Ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results, Ophthalmology, 2015;122:375–81.
16. Ishibashi T, Li X, Koh A, et al., The REVEAL Study: Ranibizumab Monotherapy or Combined with Laser versus Laser Monotherapy in Asian Patients with Diabetic Macular Edema, Ophthalmology, 2015;122:1402–15.
17. López-Gálvez MI, Arias L, Roura M, Efficacy and safety profile of ranibizumab versus laser photocoagulation in patients with diabetic macular edema. Re-Des Study, Ophthalmologica, 2014;232:15.
18. Mitchell P, Bandello F, Schmidt-Erfurth U, et al., The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema, Ophthalmology, 2011;118:615–25.
19. Régnier S, Malcolm W, Allen F, et al., Efficacy of anti-VEGF and laser photocoagulation in the treatment of visual impairment due to diabetic macular edema: a systematic review and network meta-analysis, PloS one, 2014;9:e102309.
20. Hutton D, Newman-Casey PA, Tavag M, et al., Switching to less expensive blindness drug could save medicare part B $18 billion over a ten-year period, Health Aff (Millwood), 2014;33:931–9.
21. Pershing S, Enns EA, Matesic B, et al., Cost-effectiveness of treatment of diabetic macular edema, Ann Intern Med, 2014;160:18–29.
22. Shaughnessy AF, Monoclonal antibodies: magic bullets with a hefty price tag, BMJ, 2012;345:e8346.
23. Campochiaro PA, Khanani A, Singer M, et al., Enhanced Benefit in Diabetic Macular Edema from AKB-9778 Tie2 Activation Combined with Vascular Endothelial Growth Factor Suppression, Ophthalmology, 2016;
24. Ciulla TA, Hussain RM, Ciulla LM, et al., Ranibizumab for diabetic macular edema refractory to multiple prior treatments, Retina, 2016;36:1292-7.
25. Wells JA, Glassman AR, Ayala AR, et al., Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema: Two-Year Results from a Comparative Effectiveness Randomized Clinical Trial, Ophthalmology, 2016;123:1351–9.
26. Wiley HE, Thompson DJ, Bailey C, et al., A Crossover Design for Comparative Efficacy: A 36-Week Randomized Trial of Bevacizumab and Ranibizumab for Diabetic Macular Edema, Ophthalmology, 2016;123:841–9.
27. Boyer DS, Nguyen QD, Brown DM, et al., Outcomes with As- Needed Ranibizumab after Initial Monthly Therapy: Long-Term Outcomes of the Phase III RIDE and RISE Trials, Ophthalmology, 2015;122:2504–13.e1.
28. Brown DM, Nguyen QD, Marcus DM, et al., Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE, Ophthalmology, 2013;120:2013–22.
29. Do DV, Sepah YJ, Boyer D, et al., Month-6 primary outcomes of the READ-3 study (Ranibizumab for Edema of the mAcula in Diabetes-Protocol 3 with high dose), Eye (Lond), 2015;29:1538– 44.
30. Ghanchi F, Hazel CA, South Asian diabetic macular oedema treated with ranibizumab (ADMOR)-real-life experience, Eye (Lond),2016;30:133–8.
31. Massin P, Bandello F, Garweg JG, et al., Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study, Diabetes Care, 2010;33:2399–405.
32. Menchini U, Bandello F, De Angelis V, et al., Ranibizumab for Visual Impairment due to Diabetic Macular Edema: Real-World Evidence in the Italian Population (PRIDE Study), J Ophthal, 2015;2015:324841.
33. Nguyen QD, Shah SM, Heier JS, et al., Primary End Point (Six Months) Results of the Ranibizumab for Edema of the mAcula in diabetes (READ-2) study, Ophthalmology, 2009;116:2175–81.e1.
34. Pearce I, Banerjee S, Burton BJL, et al., Ranibizumab 0.5 mg for Diabetic Macular Edema with Bimonthly Monitoring after a Phase of Initial Treatment: 18-Month, Multicenter, Phase IIIB RELIGHT Study, Ophthalmology, 2015;122:1811–9.
35. Prünte C, Fajnkuchen F, Mahmood S, et al., Ranibizumab 0.5 mg treat-and-extend regimen for diabetic macular oedema: the RETAIN study, Br J Ophthalmol, 2016;100:787–95.
36. Dhoot DS, Pieramici DJ, Nasir M, et al., Residual edema evaluation with ranibizumab 0.5 mg and 2.0 mg formulations for diabetic macular edema (REEF study), Eye (Lond), 2015;29:534–41.
37. Bressler NM, Varma R, Suner IJ, et al., Vision-Related Function after Ranibizumab Treatment for Diabetic Macular Edema, Ophthalmology, 2014;121:2461–72.
38. Brown GC, Brown MM, Turpcu A, et al., The Cost-Effectiveness of Ranibizumab for the Treatment of Diabetic Macular Edema, Ophthalmology, 2015;122:1416–25.
39. Régnier SA, Malcolm W, Haig J, et al., Cost-effectiveness of ranibizumab versus aflibercept in the treatment of visual impairment due to diabetic macular edema: a UK healthcare perspective, CEOR, 2015;7:235–47.
40. Zhang X, Saaddine JB, Chou CF, et al., Prevalence of diabetic retinopathy in the United States, 2005-2008, JAMA, 2010;304:649–56.
41. Hernandez C, Candell-Riera J, Ciudin A, et al., Prevalence and risk factors accounting for true silent myocardial ischemia: a pilot case-control study comparing type 2 diabetic with nondiabetic control subjects, Cardiovasc Diabetol, 2011;10:9.
Keywords: Ranibizumab, diabetic macular oedema,cost-effectiveness